Formulations such as injections, transdermal formulations, and oral formulations are used to administer medicinal agents to the circulatory system in the body. Of these formulations, oral formulations are advantageous in that there is no pain as in injections and such, but may have low intestinal absorption depending on the type of disease or drug used for the disease. Moreover, acid in some oral formulations may decompose medicinal agents, leading to unsatisfactory efficacy. Thus, there is a need for pharmaceutical agents that enable efficient absorption of intestinal absorptive drugs such as oral formulations or suppositories. Especially in the field of antitumor agents, progress has been made in the development of various oral formulations, in addition to injections, and there is a need to develop efficient methods for using them.
Various tumors exist, such as stomach cancer, esophageal cancer, liver cancer, colon cancer, rectal cancer, pancreatic cancer, lung cancer, thyroid cancer, breast cancer, ovarian cancer, cervical cancer, endometrial cancer, ovarian cancer, tongue cancer, lip cancer, pharyngeal cancer, laryngeal cancer, oral cancer, lung cancer, skin cancer, malignant melanoma, rhabdomyosarcoma, ureteral tumor, bladder cancer, prostate cancer, testicular tumor, malignant lymphoma, leukemia, myeloma, bone tumor, nervous system tumor, and glioma.
Various antitumor agents have been developed for these tumors in chemotherapy. Specifically, antitumor agents such as the following have been developed:
alkylating agents that destroy cancer cell DNA or inhibit DNA replication by introducing an alkyl group;
antimetabolites that suppress the proliferation of cancer cells by inhibiting the metabolism of cancer cells and thereby impairing their functions;
antitumor antibiotics that are obtained from natural microorganisms and exhibit antitumor activity such as destroying the membranes of cancer cells, decomposing DNA, or inhibiting DNA synthesis;
plant preparations that stop cell division and cause cell damage by plant alkaloids obtained from plants;
hormone preparations that exhibit antitumor activity, in which hormonal agents with opposite activities, or hormonal antagonists, bind to hormone-binding sites on cancer cells in advance to the binding of hormones;
immunoadjuvants for activating the immune system;
immunotherapeutic agents that are used for regulating or enhancing immune response to cancer, such as cytokines;
platinum formulations that inhibit the cell division of cancer cells by binding to their DNA; and
other antitumor agents that are not categorized as above, such as kinase inhibitors, histamine A derivatives, Actinomyces aminopeptidases, mannitol derivatives that exhibit activity similar to alkylating agents and antimetabolites, enzyme preparations that decompose L-asparagine in the blood and thereby render asparagine-requiring tumor cells deficient in nutrition, bisdioxopiperazine derivatives, and aceglatone which suppresses recurrent bladder tumor.
Various therapeutic methods such as surgical therapy, radiotherapy, proton beam therapy, immunotherapy, lymphocyte therapy, gene therapy, and thermotherapy have also been developed and used in combination, resulting in improved therapeutic effects.
In cancer therapy that administers antitumor agents, various formulations such as injections, oral formulations, suppositories, patches, and ointments have been developed; however, the majority of these formulations are injections and oral formulations, and in particular, most antitumor formulations are mainly injections, such as interferon and platinum antitumor agents. Absorption of antitumor agents is difficult in oral formulations, suppositories, patches, and ointments, and with oral formulations, many antitumor agents are decomposed by acids leading to unsatisfactory efficacy. Therefore, even for antitumor agents that require long-term administration, painful injections that impose a great burden on patients are inevitably used at present.
The following documents are for oral administration of antitumor agents or improvement of their efficacy by oral administration: an antitumor platinum complex that can be administered orally (Patent Documents 1 to 2), (Patent Documents 3 to 4); a hard capsule formulation of cytarabine ocfosphate for oral administration, which comprises a polymer that acts as a disintegrator and alkali (Patent Document 5); a formulation for mucosal administration, which comprises bicalutamide in a solid dispersion comprising an enteric polymer with a pKa of 3 to 6 (Patent Document 6); and a composition for oral administration comprising a dispersion/mixture of bioactive peptides in multivalent metal compound carriers (Patent Document 7).
Although not related to oral administration, the following have also been disclosed: a method for suppressing tumor growth by injecting hydroxyapatites with an average particle size of 10 to 1000 μm, to which an antitumor agent has been adsorbed, into an artery leading to a tumor site, and retaining the hydroxyapatites as a microembolus within the tumor, thereby stopping the nutrient supply to the tumor and at the same time, maintaining a high concentration of the antitumor agent at the tumor site for a long period of time (Patent Document 8); a method for controlled release of an antitumor agent by implanting into the body, hydroxyapatites with an average particle size of 100 to 500 μm filled with the antitumor agent (Patent Document 9); a method for promoting or delaying the effect of a drug, or selectively adsorbing various cells such as cancer cells, viruses such as AIDS, ATL, and hepatitis viruses and so on to control their differentiation and/or proliferation and to enable the drug to exert its effect, by adding a calcium phosphate microcrystal to the drug and administering it into the blood vessel (Patent Document 10); an invention using as a medical formulation for injection a hydroxyapatite microparticulated to 500 nm or less and whose surface has been treated by albumin and such (Patent Document 11); a calcium carbonate compound microparticle with a diameter of 0.1 to 200 μm used as an injection or a mucosal formulation such as nasal formulation, in which a biologically active substance is enclosed and whose surface is coated with a porous calcium phosphate-based-material (Patent Document 12). Also disclosed are a method for implanting into a tumor site hydroxyapatites of 1,250 to 1,500 μm to which an antitumor agent has been adsorbed, and then heating them for use in thermochemotherapy (Non-patent Document 1); and a method for controlled release of carboplatin that uses as a release-control agent, porous hydroxyapatites with an average particle size of 36.1 μm and surface area of 2.5 m2/g, to prepare controlled-release carboplatin, and that administers it via an intraperitoneal or intrathoracic mediastinal route (Non-patent Document 2).
However, the absorption of antitumor agents used in oral administration is poor and in many cases the intrinsic effects of these antitumor agents are not exerted. Therefore, there is a need for pharmaceutical agents that enable efficient absorption of orally administered antitumor agents.    [Patent Document 1] Japanese Patent Application Kokai Publication No. (JP-A) H8-20594    [Patent Document 2] JP-A H8-27174    [Patent Document 3] JP-A H8-113583    [Patent Document 4] JP-A H10-251285    [Patent Document 5] JP-A H6-40923    [Patent Document 6] JP-A 2004-143185    [Patent Document 7] WO98/09645    [Patent Document 8] JP-A S63-255231    [Patent Document 9] JP-A H2-200628    [Patent Document 10] JP-A H5-255095    [Patent Document 11] JP-A H6-329557    [Patent Document 12] JP-A 2004-307398    [Non-patent Document 1] Japanese Journal of Cancer and Chemotherapy 19 (10): 1644-1647, 1992    [Non-patent Document 2] Japanese Journal of Cancer and Chemotherapy 26 (12): 1791-1793, 1999